Background and Epidemiology

The most common lesion encountered in the sella will be a pituitary adenoma. Estimates of the prevalence of pituitary adenomas vary widely between studies, which are performed using either MRI or autopsy findings. A recent meta-analysis found a prevalence of 22.5% in imaging studies (range 1%–40%) and 14.4% in postmortem studies (range 1%–35%), for an overall prevalence of 16.7%.¹ The vast majority of pituitary adenomas are microadenomas (diameter <1 cm). Macroadenomas are far less common, and their prevalence in the population is estimated to be approximately 0.2%.¹ Macroadenomas make up a much larger proportion of adenomas that come to clinical attention, however. A cross-sectional study of 81,149 patients in Banbury, UK found the overall prevalence of known pituitary tumors to be 77.6 cases per 100,000 inhabitants (or 63 total cases). Of these, only 7 were found incidentally. The others presented with some sort of clinical symptomatology, and of those, 41% were macroadenomas.²

The prevalence of “functional tumors”—adenomas that hypersecrete hormones resulting in a clinical syndrome—is in the range of 50% to 60% of all clinically apparent pituitary tumors. The most common functional or secretory tumors are prolactinomas (approximately 40%), followed by ACTH-secreting tumors (14%), growth hormone (GH)–secreting tumors (5%), and TSH-secreting tumors and mixed tumors (both under 1%).³ Many “nonfunctional” tumors are clinically silent gonadotroph adenomas, while a small proportion of these produce but do not secrete ACTH, GH, or TSH.

The majority of pituitary tumors remain stable after their initial detection. In one meta-analysis of eight studies including 144 patients who were followed from 2 to 8 years, 84% of microadenomas of the pituitary gland remained stable in size. A few (6%) regressed and approximately 10% increased in size. In contrast, 20% of macroadenomas grew (11% of those were due to apoplexy), 11% diminished in size, and 69% remained stable.⁴

Pathogenesis

A great deal has been learned about the pathogenesis of some pituitary lesions but the pathogenesis of the majority of pituitary and parasellar lesions is still unknown. It is clear there are a variety of molecular mechanisms responsible for neoplastic transformation. Pituitary adenomas arise from adenohypophysial cells of the anterior pituitary. The vast majority of pituitary tumors are thought to be benign. Adenomas can, however invade local structures including the dura of the sella, local bony structures, and the sphenoid sinus cavity. Pituitary carcinoma, defined by the presence of local discontinuous or systemic spread, is extremely rare and probably represents approximately 0.2% to 0.5% of all pituitary lesions.⁵ Pituitary neoplasms are monoclonal, and outside of defined genetic syndromes, their cause is not well understood.

At least five genes have been identified as causes of pituitary adenomas with four of them comprising familial pituitary tumor syndromes: MEN1, PRKAR1A, CDKN1B, and AIP. Genetic disorders such as MEN1 (a mutation in the MENIN protein that reverses function of tumor suppressor gene), and Carney’s complex (PRKAR1A, insufficient activity of protein kinase-A regulatory subunit 1) are examples of models for pituitary tumor development. The CDKN1B gene causes a MEN-like syndrome (MEN4) associated with hyperparathyroidism and other rare tumors.⁶ Another recently discovered mutation is located in the AIP (aryl hydrocarbon receptor–interacting protein) gene (11q13).^7,8 This appears to act as a tumor suppressor gene and mutations predispose to GH-secreting pituitary tumors.^7,9,10 Approximately 40% of sporadic GH-secreting adenomas are associated with a somatic mutation in the Gs alpha gene.^11,12 The mutation results in constitutive activation of the cAMP/PKA signal transduction pathway and leads to neoplastic transformation of somatotroph cells of the pituitary.^13,14

Clinical Presentation

Pituitary and parasellar lesions may come to attention in a variety of ways. They may be detected incidentally on radiographic scans obtained for unrelated reasons, or as a result of clinical symptoms and signs attributable to either endocrine dysfunction or to mass effect. Clinical syndromes of hormone excess result from hypersecretion of prolactin, growth hormone, ACTH or TSH causing the amenorrhea/galactorrhea syndrome, acromegaly, Cushing’s disease, or secondary hyperthyroidism, respectively. Rarely, patients have clinical features of gonadotropin excess. Mass effect symptoms and signs may include headache, visual field loss, diplopia, facial pain, and epistaxis, as well as CSF leaks. Further, varying degrees of hypopituitarism due to compressive injury may result in partial or complete loss of pituitary function. Thus, careful hormonal, neuroradiologic, and ophthalmologic assessments are essential in the evaluation of patients affected by these tumors.

The Initial Evaluation

The initial evaluation of patients with pituitary tumors begins with a general history and physical examination in order to determine if there are co-morbidities or other medical issues that will affect the evaluation and management of the pituitary patient. Surgical risk is determined and appropriate consultations are obtained when necessary. For example, patients with acromegaly and sleep apnea may require evaluation by a pulmonologist prior to surgery. Diabetes and hypertension in acromegalic and Cushingoid patients may require treatment to decrease surgical morbidity. A thorough assessment of the clinical manifestations of the disease process may guide the selection of subsequent laboratory and radiological studies. Laboratory assessment of the hormonal status of affected patients allows for determination of a specific diagnosis, subsequent treatment planning, and permits decisions as to whether or not hormone replacements are necessary.

Laboratory Investigations

The most appropriate screening tests for an incidentally discovered pituitary lesion are the topic of much debate.^15,16 A survey of endocrinologists in the United States and United Kingdom suggested that, when confronted with a microadenoma, a range of 0 to 16 tests would be ordered (median 7).^16,17 Most experts would advocate screening for both pituitary insufficiency and hormone excess as both states are relevant in the initial decision-making and also the long term follow-up of patients. This information is particularly important in the context of a preoperative evaluation. Clinical findings should guide medical decision-making. For example, patients who are obviously Cushingoid will require specific testing of adrenal function that may not be conducted in those who appear to have acromegaly.

Source: Adapted from Mancini T, Casanueva FF, Giustina A. Hyperprolactinemia and prolactinomas. Endocrinol Metab Clin North Am. 2008;37:67-99, viii.

A small subset of extremely large prolactinomas can produce enormous amounts of prolactin that overwhelm antibodies used in the assay resulting in a false lowering of prolactin levels.²⁶ This is known as the “hook effect.” In the setting of a macroadenoma, when a prolactinoma is suspected, prolactin levels should be performed on diluted serum samples to avoid this error in laboratory diagnosis. Most modern radioimmunoassays are able to detect prolactin levels as great as 4000 μg/l without being subject to the “hook effect.” We recommend that treating physicians being aware of the prolactin test performance in the laboratories they employ to evaluate their patients.²⁷

On occasion a patient will be found to have an elevated prolactin but without symptoms of hyperprolactinemia. This is often due to a condition known as macroprolactinemia. In this disorder, prolactin aggregates with circulating IgG antibodies resulting in decreased clearance of the complex and thus elevated prolactin levels.^28–30 However, the prolactin-IgG complex is devoid of biological activity and thus the absence of symptoms. This condition does not require treatment and needs to be distinguished from true hyperprolactinemia. Incubating the serum with polyethylene glycol, which removes the prolactin-IgG complex prior to performing the assay, can identify the phenomenon.

Cushing’s Disease

Cushing’s disease is a term applied to a specific form of Cushing’s syndrome (pathological hypercortisolism) caused by an ACTH-secreting pituitary tumor. Cushing’s syndrome may be due to a variety of other disorders including the syndrome of ectopic ACTH secretion, adrenal tumors, and exogenous glucocorticoid therapy for non-endocrine disease processes. Due to the risks that hypercortisolism can pose in the perioperative period, including deep venous thrombosis, pneumocystis pneumonia and other infections, poor wound healing as well as steroid hormone withdrawal in the postoperative period, most would have a low threshold to screen for Cushing’s prior to pituitary surgery.

Recent guidelines review proposed diagnostic approaches to the evaluation of patients with suspected Cushing’s syndrome.³¹ The inclusion of an endocrinologist experienced with this disorder to establish and confirm the diagnosis is strongly advised. Generally speaking, and depending on the clinical situation, one should start with screening tests, then proceed to diagnostic or confirmatory tests, and finally, to differential diagnostic tests.

There are at least three reliable screening tests to evaluate patients with suspected hypercortisolism. Keep in mind that screening tests are designed to be sensitive but not specific. Thus, there will be false positive tests and not everyone with a positive screening test will be ultimately diagnosed with pathologic hypercortisolism. Appropriate screening tests include the overnight 1 mg dexamethasone suppression test, the 24-hour urine collection for free cortisol and creatinine, and the midnight salivary cortisol collection.^32–36 For most patients who require screening only, performance of one of these tests is indicated. The salivary cortisol and 24-hour urine free cortisol collection should be done at least twice to confirm abnormal initial findings. A positive dexamethasone suppression test is identified when an 8 a.m. cortisol is greater than 1.8 μg/dl following administration of 1 mg of dexamethasone at 11 p.m. the prior night. Using this cutoff gives the test a sensitivity of approximately 95% with specificity of 80%. To enhance specificity to over 95%, a cutoff of 5 μg/dl may be used, which will sacrifice sensitivity (falling to 85%).³¹ A 24-hour urine cortisol above the upper limits of normal may be considered a positive screening test, along with a late-night salivary cortisol level of 4 nmol/l or greater.³¹

Diagnostic tests are designed to balance sensitivity and specificity. They are used to confirm the diagnosis of pathologic hypercortisolism. Diagnostic tests for hypercortisolism include the 24-hour urine cortisol, the dexamethasone suppressed CRH stimulation test, (CRH/Dex test) and the formal low-dose dexamethasone suppression test.^37,38 A 24-hour urine cortisol excretion rates greater than two to three times the upper limit of normal is generally considered to be a positive test. The CRH/Dex test is performed by administering dexamethasone, 0.5 mg every 6 hours for 2 days followed by CRH stimulation on the morning of the third day. A cortisol value greater than 1.4 μg/dl 15 minutes after CRH administration indicates an abnormal result.³⁹ Treating physicians are encouraged to review the performance of tests employed by their laboratory and draw upon their own experiences to determine what constitutes an abnormal response to a formal dexamethasone suppression test.